Activation of uridine uptake is an early event in the mitogenic response, occurring within minutes of mitogenic stimulation of quiescent 3T3 mouse fibroblasts, compared with DNA synthesis which occurs 10-15 hours later. Data from our Laboratory indicate that the early activation of pyrimidine nucleotide synthesis is linked to the synthesis of components of the extracellular matrix (specifically, hyaluronate). Hyaluronate has been implicated as a factor involved in tumor invasion and metastasis. Thus elucidation of cellular regulatory mechanisms that control the synthesis of oligosaccharide moieties of extracellular matrix components could be useful to the discovery of agents with anti-invasive and anti-metastatic properties. Chromatographic analysis of the nucleotide pool in 3T3 fibroblasts 30 minutes after serum stimulation revealed an increase in UDP-glucuronide that corresponded to the increase in uridine uptake with regard to time course and magnitude. Other factors capable of stimulating uridine uptake, including EGF, PDGF, IL-1, and phorbol ester also caused an increase in UDP-glucuronide. Certain growth factors and various combinations of growth factors stimulated 3T3 fibroblasts to secrete hyaluronate. Of particular interest was the finding that conditioned media from a BT-20 human breast carcinoma (whose oncogene product is PDGF) stimulates hyaluronate synthesis by fibroblasts indicating intercellular communication between tumor and normal fibroblasts in the synthesis of hyaluronate induced by this human tumor. Studies into the biochemical mechanism for mitogen-stimulation of hyaluronate synthesis indicate that UDP-glucose dehydrogenase activity is increased following mitogen-stimulation of quiescent fibroblasts. This stimulation is an early event following mitogenic activation. Current studies are focusing on the regulatory role of UDP-xylose in the synthesis of proteoglycans and glycosaminoglycans.